Abstract
Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic “neurocentric” view of Alzheimer’s disease (AD), being astrocytes increasingly considered a key player in this neurodegenerative disease. AD, the most common form of dementia in the elderly, is characterized by a deterioration of memory and of other cognitive functions. Although, early cognitive deficits have been associated with synaptic loss and dysfunction caused by amyloid-β peptides (Aβ), accumulating evidences support a role of astrocytes in AD. Astrocyte atrophy and reactivity occurring at early and later stages of AD, respectively, involve morphological alterations that translate into functional changes. However, the main signals responsible for astrocytic alterations in AD and their impact on synaptic function remain to be defined. One possible candidate is adenosine, which can be formed upon extracellular catabolism of ATP released by astrocytes. Adenosine can act as a homeostatic modulator and also as a neuromodulator at the synaptic level, through the activation of adenosine receptors, mainly of A1R and A2AR subtypes. These receptors are also present in astrocytes, being particularly relevant in pathological conditions, to control the morphofunctional responses of astrocytes. Here, we will focus on the role of A2AR, since they are particularly associated with neurodegeneration and also with memory processes. Furthermore, A2AR levels are increased in the AD brain, namely in astrocytes where they can control key astrocytic functions. Thus, unveiling the role of A2AR in astrocytes function might shed light on novel therapeutic strategies for AD.
Highlights
Reviewed by: Alexei Verkhratsky, The University of Manchester, United Kingdom Isadora Matias, Federal University of Rio de Janeiro, Brazil
Adenosine can be released directly via equilibrative nucleoside transporters (ENT), such as ENT-1 and ENT-2, being the intracellular levels of this nucleoside controlled by the activity of adenosine kinase (ADK), which is mainly expressed in astrocytes and metabolize the conversion of adenosine into AMP (Boison et al, 2010)
There is evidence supporting a correlation between the adenosine sources and the type of adenosine receptors that are activated, insofar as it was described that A1R are mainly activated by the tonus of adenosine, formed from the catabolism of ATP released from astrocytes (Pascual et al, 2005) and by postsynaptic adenosine efflux (Lovatt et al, 2012), whereas adenosine derived from synaptically-released ATP, due to CD73 action, mainly activates neuronal, mainly postsynaptic, A2A receptors (A2AR) (Cunha et al, 1995; Rebola et al, 2008; Augusto et al, 2013; Carmo et al, 2019; Gonçalves et al, 2019)
Summary
Reviewed by: Alexei Verkhratsky, The University of Manchester, United Kingdom Isadora Matias, Federal University of Rio de Janeiro, Brazil. Adenosine’s effects in the brain are mostly mediated by A1R and A2AR, which prime role is the modulation of synaptic activity, interfering with information transmission within neuronal circuits (reviewed in Fredholm et al, 2005; Cunha et al, 2008; Agostinho et al, 2020).
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